SAMJ, S. Afr. med. j. vol.103 no.10 Cape Town Jan. 2013

Professors Schaaf and Cotton both work in the Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa; Professor Boon at the Department of Paediatrics and Child Health, Faculty of Health Sciences, Walter Sisulu University, East London, South Africa; and Professor Jeena at the Department of Paediatrics and Child Health, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa. They co-authored this guideline on behalf of the Paediatric Essential Medicines List Committee of the National Department of Health

Isoniazid preventive therapy (IPT) prevents tuberculosis (TB) in immunocompetent children <5 years of age after exposure to an infectious TB source case. Routine IPT has been advocated in all HIV-infected children without TB, but has been controversial. Antiretroviral therapy markedly reduces the risk for TB in HIV-infected children, especially when started early in infancy. In HIV-infected children, as in HIV-uninfected children, we recommend post-exposure IPT after each TB exposure episode; but in HIV-infected children, this should be given irrespective of age or antiretroviral therapy. However, evidence for routine IPT without known exposure to TB in HIV-infected children is not convincing and is therefore not recommended.

Isoniazid preventive therapy (IPT) effectively prevents tuberculosis (TB) in immunocompetent children <5 years of age, but its use in HIV-infected children remains controversial despite many studies and guidelines.

Recent World Health Organization (WHO) guidelines for IPT in HIV-infected children exclude infants (<12 months of age) from pre-exposure IPT (i.e. IPT before known exposure to TB), based mainly on a large randomised double-blinded study that found no benefit in the first years of life.[1,2] IPT is recommended for older children, based on another randomised double-blinded study and supported by a cohort study of the same and additional children over a longer time period.[1,3,4]

However, it is known from the pre-treatment era and from a study in the HIV era in a high TB incidence area that infants infected with Mycobacterium tuberculosis in the first year of life are at greatest risk of developing TB.[5,6] If infants <12 months of age showed no benefit from pre-exposure IPT, it would seem unlikely that older children would benefit, although unrecognised exposure from outside the household is more likely in older children than in infants.[7]

The cohort study by Frigati et al.[4] showed that the most benefit for preventing TB was from starting antiretroviral therapy (ART), which reduced the risk for TB by 32%. Other studies in children and adults support ART significantly reducing the risk of TB disease after infection.[8-10] The cohort study,[4] a continuation of the study by Zar et al.,[3] also suggested a trend towards the benefit of adding IPT, unlike the study by Madhi et al.[2] In both studies, children exposed to TB were switched to open-label IPT.[2-4] Children receiving open-label IPT in the Madhi study were discontinued. In the study by Zar et al., while still in the double-blinded phase (isoniazid v. placebo), there was additional benefit in adding IPT as children were re-assigned to isoniazid v. placebo after receiving open-label IPT.[2,4] Other differences between the studies included severity of disease, availability of ART at baseline, ability to closely monitor adherence and size of the studies, which may account for confusion around the IPT policy for South Africa.

Most HIV-infected infants and children in South Africa should access ART as early as 8 - 10 weeks after birth, which should protect them to a large extent from developing TB as they would be immunologically similar to children without HIV infection. Hence, the possible benefits of IPT need to be weighed against possible risks, especially when considering pre-exposure IPT.

Le Roux et al.[11] showed long-term IPT together with ART to be relatively safe in HIV-infected children; only 3.4% of children on ART and IPT developed grade 3 and 4 transaminase response, although none developed jaundice. However, the risk of hepatotoxicity and of developing isoniazid resistance if undiagnosed TB disease is treated with isoniazid alone is real.

Advice from various international and South African guidelines has caused uncertainty as to whether IPT should be given to all children without TB disease at initiation of ART.[1,12-14] Consequently, there is much uncertainty among healthcare workers (HCWs) in terms of IPT implementation. Therefore, the Paediatric Essential Medicines List Committee supported by the National Department of Health's HIV/AIDS, TB and Maternal, Child and Women's Health (HIV/AIDS, TB & MCWH) branch provide (on weighing current evidence and the risks/benefits) the following national guideline for IPT in HIV-infected and HIV-uninfected children:

1. In HIV-infected children, ART should start as early as possible in infancy. Early ART has an important protective effect against the development of TB following infection with M. tuberculosis.

2. Post-exposure IPT 10 mg/kg daily for 6 months is recommended in the following children after exclusion of TB disease:

HIV-uninfected children less than 5 years of age

HIV-infected children irrespective of age or ART status.

Post-exposure means close contact with an infectious pulmonary TB case (defined as a sputum microscopy smear-positive or culture-positive or Genexpert-positive case) or the child is Mantoux tuberculin skin test-positive (induration ≥10 mm or, if HIV-infected, ≥5 mm) in the absence of previous IPT or TB treatment.

IPT should be repeated with each significant new exposure (isoniazid has no post-antibiotic effect, therefore no long-term protective effect after completing IPT).

In this regard, all HCWs should enquire about any new TB contact (new close TB source cases) at every follow-up visit, as well as asking caregivers about their own health, to screen for possible TB symptoms.

3. Pre-exposure IPT is not recommended in any HIV-infected or -uninfected child.

4. Post-TB disease IPT is not recommended. Ensure when treating TB in children that cure is complete. If resolution of TB is incomplete, exclude drug-resistant TB disease (culture and drug susceptibility testing supported by Genexpert tests) and, if no drug-resistant TB is found, consider prolonging the continuation phase to 7 months as provided for in the Essential Drug List in case of extensive disease or slow response to TB treatment. Repeated exposure to TB is managed with exclusion of TB disease and IPT as indicated as per point 2 above.

5. Post-exposure preventive therapy in children (HIV-uninfected or HIV-infected) who are exposed to drug-resistant infectious TB cases:

5.2. INH monoresistant contacts: RIF 10 - 15 mg/kg for 4 months as single drug (or in RIF/isoniazid if single drug RIF not available at the same RIF dose).

5.3. Multidrug-resistant and extensive drug-resistant TB contacts: Evidence for preventive therapy is less clear and expert advice should be sought. Two recent publications address this situation.[15,16]